Phase 1 study of tasquinimod, an S100A9 inhibitor, alone and in combination with IRd for relapsed and refractory multiple myeloma (RRMM).
Authors: Dan T. Vogl, Yulia Nefedova, E. Paul Wileyto, Chau T. Nguyen, Cynthia Diaczynsky, Abigail Etzweiler, Inna Strakovsky, Cindy Lin, Eva Bondesson, Helen Tuvesson, Erik Vahtola, Adam D. Cohen, Sandra P. Susanibar-Adaniya, Adam J. Waxman, Alfred L. Garfall, Edward Allen Stadtmauer
Journal: Journal of Clinical Oncology (2023)

8042 Background: S100A9, a protein produced by myeloid-derived suppressor cells (MDSCs) in the bone marrow microenvironment, promotes multiple myeloma (MM) progression and confers therapeutic resistance. Tasquinimod (tasq), an oral S100A9 inhibitor, has pre-clinical anti-myeloma effects alone and combined with proteasome inhibitor (PI) and immunomodulator (Imid) therapy (Lin C, EHA 2020: EP896). Tasq previously improved PFS in prostate cancer patients (pts) (JCO 2016;34(22):2636-43). We are conducting a phase 1 trial (NCT04405167) of tasq as a single agent and in combination with ixazomib (ixa), lenalidomide (len), and dexamethasone (dex) (IRd) in pts with RRMM. Methods: We enrolled pts with RRMM refractory to, intolerant of, or with contraindication to len, pomalidomide (pom), bortezomib, carfilzomib (cfz), and a CD38 monoclonal antibody. Tasq was given in 28-day cycles as shown below, with a 3+3 dose escalation scheme. For combination therapy, pts received ixa (4 mg days 1/8/15), len (25 mg days 1-21, with adjustments for renal dysfunction), and dex (40 mg qwk). Results: Of 15 pts, median age was 70y (range 56-84); 53% were male; 27% were African American and 73% Caucasian. Pts had received a median of 8 prior lines of therapy (range 4-17), and all were refractory to ≥1 Imid, 87% to ≥1 PI, and 100% to a CD38 mAb, with 87% triple class refractory and penta-exposed. 10 pts received single-agent tasq at dose levels 1 (3 pts), 2 (3 pts), and 3 (4 pts). The most common treatment-emergent adverse events (TEAEs) were fatigue (all grade [gr] 1/2), anemia (5 pts, gr 3 in 2), anorexia (5 pts, gr 3 in 2), pain (5 pts, all gr 1/2), nausea/vomiting (4 pts, all gr 1/2), and neuropathy (3 pts, all gr 1/2). No dose-limiting toxicities (DLTs) were observed, but at dose level 3, 2 pts stopped for intolerable toxicities, and we identified dose level 2 as the single-agent MTD. 5 pts have received tasq with IRd at dose levels 1 (3 pts) and 2 (2 pts). Gr &gt; = 3 TEAEs were gr 4 thrombocytopenia in 1 pt (improved with dose reductions of ixa and len), gr 3 insomnia in 1 pt, and gr 5 COVID pneumonia in 1 pt. No tasq-related DLTs were observed. On single-agent tasq, 3 pts with progressive disease at study entry had stabilization of serum markers while on study. Of 5 pts on the IRd combination, 1 has had a partial response that is ongoing after 10 months, despite being previously refractory to ixa/pom and cfz/pom combinations. Conclusions: Tasquinimod, an S100A9 inhibitor, is well tolerated in pts with RRMM as a single-agent and in combination with IRd, with a single-agent MTD of 1 mg daily after a 1-week dose escalation. Tasq has anti-myeloma activity in combination with IRd, as evidenced by a partial response in a patient previously refractory to Imid/PI combination therapy. Enrollment continues to tasq with IRd at dose level 2. Clinical trial information: NCT04405167 . [Table: see text]